The success of anti-PD-1 with chemotherapy for esophageal squamous cell carcinoma
Authors: Hanneke W.M. van Laarhoven, Sarah Derks
Journal: Cell Reports Medicine (2023)

In the ASTRUM-007 randomized double-blind phase III study, Song et al.1Song Y. Zhang B. Xin D. Kou X. Tan Z. Zhang S. Sun M. Zhou J. Fan M. Zhang M. et al.First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial.Nat. Med. 2023; 29: 473-482Crossref PubMed Scopus (8) Google Scholar showed that the combination of PD-1 inhibitors with first-line fluoropyrimidine and platinum-based chemotherapy improves outcomes in PD-L1-overexpressing esophageal squamous cell carcinomas. In the ASTRUM-007 randomized double-blind phase III study, Song et al.1Song Y. Zhang B. Xin D. Kou X. Tan Z. Zhang S. Sun M. Zhou J. Fan M. Zhang M. et al.First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial.Nat. Med. 2023; 29: 473-482Crossref PubMed Scopus (8) Google Scholar showed that the combination of PD-1 inhibitors with first-line fluoropyrimidine and platinum-based chemotherapy improves outcomes in PD-L1-overexpressing esophageal squamous cell carcinomas. For a long time, advances in immunotherapy had not reached patients with esophageal cancer. Until recently, to guide first line treatment, no randomized phase III studies were available, and treatment recommendations were based on small phase II studies or derived from results of phase III randomized studies that included adenocarcinoma patients or a mix of both histologies.2Janmaat V.T. Steyerberg E.W. van der Gaast A. Mathijssen R.H. Bruno M.J. Peppelenbosch M.P. Kuipers E.J. Spaander M.C. Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer.Cochrane Database Syst. Rev. 2017; 2017Google Scholar The randomized KEYNOTE-590, CHECKMATE-648, and ESCORT-1 studies have importantly changed the treatment landscape, and the current ASTRUM-007 study adds to this existing body of evidence.1Song Y. Zhang B. Xin D. Kou X. Tan Z. Zhang S. Sun M. Zhou J. Fan M. Zhang M. et al.First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial.Nat. Med. 2023; 29: 473-482Crossref PubMed Scopus (8) Google Scholar,3Sun J.-M. Shen L. Shah M.A. Enzinger P. Adenis A. Doi T. Kojima T. Metges J.P. Li Z. Kim S.B. et al.Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.Lancet. 2021; 398: 759-771Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar,4Doki Y. Ajani J.A. Kato K. Xu J. Wyrwicz L. Motoyama S. Ogata T. Kawakami H. Hsu C.H. Adenis A. et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N. Engl. J. Med. 2022; 386: 449-462Crossref PubMed Scopus (259) Google Scholar,5Luo H. Lu J. Bai Y. Mao T. Wang J. Fan Q. Zhang Y. Zhao K. Chen Z. Gao S. et al.ESCORT—1st Investigators effect of Camrelizumab vs. Placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the ESCORT-1st randomized Clinical trial.JAMA. 2021; 326: 916-925Crossref PubMed Scopus (207) Google Scholar ASTRUM-007 is a randomized double-blind phase III study to test the additive effect of anti-programmed cell death protein 1 (PD-1) antibody serplulimab to first-line fluoropyrimidine and platinum-based chemotherapy in patients with esophageal squamous cell carcinomas and a programmed death-ligand 1 (PD-L1) combined positivity score (CPS) ≥ 1.1Song Y. Zhang B. Xin D. Kou X. Tan Z. Zhang S. Sun M. Zhou J. Fan M. Zhang M. et al.First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial.Nat. Med. 2023; 29: 473-482Crossref PubMed Scopus (8) Google Scholar Serplulimab is a novel humanized anti-PD-1 monoclonal antibody that has already been tested and shown effectivity in multiple tumor types. In the current study, the ASTRUM consortium investigated serplulimab combined with 5-fluorouracil and cisplatin and convincingly showed improvement of median overall survival compared to placebo-chemotherapy combinations from 11.8 months to 15.3 months (hazard ratio [HR] 0.68). The difference in progression-free survival was only modest (5.3 months to 5.8 months), but overall response rates (ORRs) of 57.6% were clearly higher compared to the control arm (42.1%). The safety profile was manageable and comparable to other studies combining PD-1 targeting agents with chemotherapy. In the ASTRUM-007 study, a total of 139 (38%) patients in the serplulimab plus chemotherapy group and 95 (52%) in the placebo plus chemotherapy group received subsequent anticancer therapy; 64 (17%) in the serplulimab plus chemotherapy group and 61 (33%) in the placebo plus chemotherapy group received subsequent immunotherapy. Despite this 33% of patients from the control group being treated with immunotherapy in second line, serplulimab added to chemotherapy as a first-line treatment still provided survival benefit, which may indicate that immunotherapy is most effective in first-line treatment or when combined with fluoropyrimide and platin-based chemotherapy. Also, since almost half of the patients did not proceed to second-line treatment—a percentage which is even larger in a real-world setting6Pape M. Vissers P.A.J. de Vos-Geelen J. Hulshof M.C.C.M. Gisbertz S.S. Jeene P.M. van Laarhoven H.W.M. Verhoeven R.H.A. Treatment patterns and survival in advanced unresectable esophageal squamous cell cancer: a population-based study.Cancer Sci. 2022; 113: 1038-1046Crossref PubMed Scopus (4) Google Scholar—future studies should invest in further improvement of first-line treatment. Some differences in the design of the KEYNOTE-590, CHECKMATE-648, ESCORT-1, and ASTRUM-007 studies should be noted. The ASTRUM-007 study and ESCORT-1 included only patients from China, while the KEYNOTE-590 and CHECKMATE-648 studies contained a more mixed population of Asian and white patients. From these latter two global studies, however, no consistent differences in performance of checkpoint inhibition between Asian and non-Asian patients emerged. The chemotherapy regimens between the studies were also slightly different. ASTRUM-007 used a biweekly infusion of 5-fluorouracil 1,200 mg/m2 and cisplatin 50 mg/m2, which resulted in a higher dosage per delivery and more infusion days compared to CHECKMATE-648, which used continuous 5-fluorouracil 800 mg/m2 and cisplatin 80 mg/m2 on a four week schedule, and KEYNOTE-590, which used continuous 5-fluorouracil 800 mg/m2 and cisplatin 80 mg/m2 every 3 weeks. ESCORT-1 chose a non-fluoropyrimidine schedule consisting of paclitaxel and cisplatin. Although chemotherapy regimens have not been compared head-to-head, the side effects and efficacy across studies seem comparable. From a patient perspective, a three- or four-week schedule may be preferable, as it requires less hospital visits. Interestingly, none of these studies used oxaliplatin as a backbone, though it is generally considered less toxic than cisplatin and is regarded as a valid treatment option not only for esophageal adenocarcinoma but also for squamous cell carcinoma.7Obermannová R. Alsina M. Cervantes A. Leong T. Lordick F. Nilsson M. van Grieken N.C.T. Vogel A. Smyth E.C. ESMO Guidelines Committee. Electronic address: [email protected]Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann. Oncol. 2022; 33: 992-1004Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Previous in vitro and in vivo studies have shown that the tumor immune microenvironment may be differentially modulated by radiotherapy and specific cytotoxic or targeted agents, thus potentially influencing the efficacy checkpoint inhibitors.8van den Ende T. van den Boorn H.G. Hoonhout N.M. van Etten-Jamaludin F.S. Meijer S.L. Derks S. de Gruijl T.D. Bijlsma M.F. van Oijen M.G.H. van Laarhoven H.W.M. Priming the tumor immune microenvironment with chemo (radio) therapy: a systematic review across tumor types.Biochim. Biophys. Acta. Rev. Cancer. 2020; 1874188386Crossref PubMed Scopus (55) Google Scholar Recently presented data from KEYNOTE-859, a randomized double-blind, placebo-controlled study of pembrolizumab with fluoropyrimidine- and platinum-containing chemotherapy for advanced HER2-negative gastric or gastroesophageal cancer, suggest that, in fact, oxaliplatin may be a better backbone than cisplatin.9Rha S. Wyrwicz L. Weber P. Bai Y. Ryu M. Lee J. Rivera F. Alves G. Garrido M. Shiu K.K. et al.Pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: phase III KEYNOTE-859 study.Ann. Oncol. 2023; 34 (VP1-2023): 319-320Abstract Full Text Full Text PDF Google Scholar Another subject of debate is the use of PD-L1 expression as a biomarker. PD-L1 expression is a difficult biomarker to analyze, and no standardized cutoff value has been accepted worldwide yet. In ASTRUM-007, PD-L1 was assessed with different antibodies (22C3, 28-8, or SP263), while KEYNOTE-590, CHECKMATE-648, and ESCORT-1 exclusively used the PD-L1 IC 22C3 assay, the PD-L1 IHC 28-8 pharmDx assay, and the PD-L1 IC 6E8 assay, respectively. Different assays may provide different numbers for levels of PD-L1 expression. Furthermore, ASTRUM-007 and KEYNOTE-590 used PD-L1 CPS, while CHECKMATE-648 and ESCORT-1 used PD-L1 TPS, complicating cross-study comparisons and meta-analyses for the determination of relevant cutoff values. Nevertheless, all studies are consistent in that the success of PD-1 inhibitors is most predominant in a PD-L1-positive population. From in-depth characterization of the immune microenvironment of esophageal squamous cell carcinoma, novel biomarkers may emerge. These biomarkers may not only be used to refine the selection of patients who benefit most from PD-1 inhibition but also to contribute to the development of novel immunotherapies targeting the immunosuppressive microenvironment of esophageal squamous cell carcinoma.10Zheng Y. Chen Z. Han Y. Han L. Zou X. Zhou B. Hu R. Hao J. Bai S. Xiao H. et al.Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment.Nat. Commun. 2020; 11: 6268Crossref PubMed Scopus (142) Google Scholar Importantly, these biomarkers may also assist in the identification of patients who could stop PD-1 inhibition early. In ASTRUM-007, as well as in most other studies in esophagogastric cancer using checkpoint inhibitors in the metastatic setting, checkpoint inhibition could be continued up to two years. It is, however, unclear whether such prolonged treatment is needed to achieve long-term benefit. In view of treatment toxicity on an individual patient level, as well as financial toxicity on a societal level, shorter treatment durations are preferable, and subsequent studies should invest in the identification of biomarkers that could guide early stopping rules. In summary, ASTRUM-007 provides another layer of evidence that the addition of PD-1 inhibitors to first-line fluoropyrimidine and platinum-based chemotherapy improves outcomes in PD-L1-overexpressing esophageal squamous cell carcinomas. The results of all randomized studies now available strongly support the use of PD-1 targeting agents in this patient population. H.W.M.v.L. reports the following conflicts of interest: Consultant or advisory role: Amphera, AstraZeneca, Beigene, BMS, Daiichy-Sankyo, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier; Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier; Speaker role: Astellas, Benecke, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Travel Congress Management B.V. S.D. reports the following conflicts of interest: Consultant or advisory role: BMS; Research funding and/or medication supply: Incyte; Speaker role: Benecke, Medtalks, Novartis, Servier.